Cost-effectiveness of immune checkpoint inhibitors as a first-line therapy for advanced hepatocellular carcinoma: a systematic review.

Since 2017, immune checkpoint inhibitors (ICIs) have been available for the treatment of advanced hepatocellular carcinoma (HCC) or unresectable HCC, but their adoption into national medical insurance programs is still limited. Cost-effectiveness evidence can help to inform treatment decisions. This systematic review aimed to provide a critical summary of economic evaluations of ICIs as a treatment for advanced HCC and identify key drivers (PROSPERO 2023: CRD42023417391). The databases used included Scopus, Web of Science, PubMed, Embase, and Cochrane Central. Economic evaluations of ICIs for the treatment of advanced HCC were included. Studies were screened by two people. Of the 898 records identified, 17 articles were included. The current evidence showed that ICIs, including atezolizumab plus bevacizumab, sintilimab plus bevacizumab/bevacizumab biosimilar, nivolumab, camrelizumab plus rivoceranib, pembrolizumab plus lenvatinib, tislelizumab, durvalumab, and cabozantinib plus atezolizumab, are probably not cost-effective in comparison with tyrosine kinase inhibitors or other ICIs. The most influential parameters were price of anticancer drugs, hazard ratios for progression-free survival and overall survival, and utility for health statest. Our review demonstrated that ICIs were not a cost-effective intervention in advanced HCC. Although ICIs can significantly enhance the survival of patients with advanced HCC, decision-makers should consider the findings of economic evaluations and affordability before adoption of new therapies.

Efficacy of adjuvant-associated COVID-19 vaccines against SARS-CoV-2 variants of concern in randomized controlled trials: A systematic review and meta-analysis.

BACKGROUND: Adjuvants may enhance the efficacy of vaccines. however, the efficacy of adjuvant-associated COVID-19 vaccines (ACVs) remains unclear since the emergence of the COVID-19 pandemic. This study aimed to address this gap by conducting a systematic review and meta-analysis of the efficacy of ACVs against Severe Acute Respiratory Syndrome Coronavirus 2 CoV (SARS-CoV-2) variants of concern (VOC). METHODS: A systematic search was conducted of randomized controlled trials (RCTs) evaluating the vaccine efficacy (VE) of ACVs against VOC (alpha, beta, gamma, delta, or Omicron), up to May 27, 2023. The DerSimonian-Laird random-effects model was used to assess VE with 95% confidence intervals (CI) through meta-analysis. Cochrane Risk of Bias tools were used to assess the risk of bias in RCTs. RESULTS: Eight RCTs with 113,202 participants were included in the analysis, which incorporated 4 ACVs [Matrix-M (NVX-CoV2373), Alum (BBV152), CpG-1018/Alum (SCB-2019), and AS03 (CoVLP]). The pooled efficacy of full vaccination with ACVs against VOC was 88.0% (95% CI: 83.0-91.5). Full vaccination was effective against Alpha, Beta, Delta, and Gamma variants, with VE values of 93.66% (95% CI: 86.5-100.74), 64.70% (95% CI: 41.87-87.54), 75.95% (95% CI: 67.9-83.99), and 91.26% (95% CI: 84.35-98.17), respectively. Currently, there is a lack of RCT evidence regarding the efficacy of ACVs against the Omicron variant. CONCLUSION: In this meta-analysis, it should be that full vaccination with ACVs has high efficacy against Alpha or Gamma variants and moderate efficacy against Beta and Delta variants. Notably, with the exception of the aluminum-adjuvanted vaccine, the other ACVs had moderate to high efficacy against the SARS-CoV-2 variant. This raises concerns about the effectiveness of ACVs booster vaccinations against Omicron.

Immunogenicity and safety of adjuvant-associated COVID-19 vaccines: A systematic review and meta-analysis of randomized controlled trials.

Background: The benefits and risks of adjuvant-associated COVID-19 vaccines (ACVs) are unclear. The study aimed to assess the immunogenicity and safety of ACVs compared with controls (placebo or the same vaccine without adjuvants [NACVs]). Methods: Randomized controlled trials sourced from PubMed, EMBASE, Web of Science, and Cochrane Library were systematically reviewed. Evaluators extracted information independently. The evidence quality was assessed using random-effects models. The risk of bias was assessed using the Cochrane Risk of Bias tool. Results: Of the 33 studies, 27 analyzed immunogenicity (n = 9069, ACVs group; n = 3757, control), and 26 analyzed safety (n = 58669, ACVs groups; n = 30733 control). Compared with controls, full vaccination with ACVs produced significant immune responses (relative risk [RR] of seroneutralization reaction, 12.3; 95 % confidence interval [95 % CI], 6.92-21.89; standardized mean deviation of geometric mean titer 3.96, 95 % CI, 3.35-4.58). Additionally, ACVs produced significant immunoreactivity compared with NACVs only (P < 0.05). Furthermore, full vaccination with ACVs significantly increased the risk of local and systemic adverse reactions (AEs) compared with controls. However, vaccination with ACVs did not significantly increase the risk of systemic and localized AEs compared with vaccination with NACVs only (P > 0.05). It was observed that ACVs had a lower risk of all-cause mortality than controls (RR, 0.51; 95 % CI 0.30-0.87). It was further found that ACVs produced nAb response against all sublines of the Omicron variant, but the antibody titers were lower than those for the SARS-CoV-2 original strain. Conclusions: The findings of this meta-analysis demonstrate that ACVs may have a superior effect and an acceptable safety in preventing COVID-19. Although these results suggest the potential of ACVs, further studies are required.

Immunogenicity and effectiveness of COVID-19 booster vaccination among people living with HIV: a systematic review and meta-analysis.

Background: The effect of booster vaccinations with the coronavirus virus disease (COVID-19) vaccine on people living with HIV (PLWH) remains unknown. In this study, we aimed to investigate the immunogenicity and effectiveness of booster doses of the COVID-19 vaccine in PLWH. Methods: Literature research was done through the PubMed, Embase, Cochrane Review, and Web of Science databases up to 4 July 2023. Pooled estimates were calculated and compared using the DerSimonian and Laird method for a random effects model. Randomized control trials and observational studies were both considered for inclusion. Results: We included 35 eligible studies covering 30,154 PLWH. The pooled immune response rate (IRR) of PLWH after the COVID-19 booster vaccination was 97.25% (95% confidence interval [CI], 93.81-99.49), and similar to healthy control (HC) (risk ratio [RR] = 0.98, 95% CI, 0.96-1.00). The pooled IRR for PLWH with CD4+ T-cell counts ≤ 200 was 86.27 (95% CI, 65.35-99.07). For Omicron variants, the pooled IRR for PLWH after booster dose was 74.07% (95% CI, 58.83-89.30), and the risk of IRR was reduced by 10% in PLWH compared with HC (RR = 0.90, 95% CI, 0.80-1.00). The T-cell immune response of PLWH was found to be comparable to HC (p ≥ 0.05). Subgroup analyses revealed that mRNA vaccines produced a relatively high IRR in PLWH compared to other vaccines. In addition, the results showed that booster vaccination appeared to further reduce the risk of COVID-19-related infections, hospitalizations, and deaths compared with the primary vaccination. Conclusion: It was shown that booster vaccination with the COVID-19 vaccine provided a high IRR in PLWH and still produced a desirable moderate IRR in PLWH with a CD4+ T-cell count of ≤ 200. Importantly, the humoral and T-cell responses to booster vaccination in PLWH were comparable to HC, and similar results were observed with the SARS-CoV-2 Omicron variant. Our review strongly emphasizes the effect of mRNA vaccine booster vaccination in PLWH on eliciting desirable protective IRR. Furthermore, booster vaccination appears to further reduce the risk of COVID-19 infection, hospitalization, and death in PLWH compared to primary vaccination. However, more evidence is needed to confirm its effectiveness.

Isoforskolin modulates AQP4-SPP1-PIK3C3 related pathway for chronic obstructive pulmonary disease via cAMP signaling.

BACKGROUND: Cyclic adenosine monophosphate (cAMP) levels are directly activated by adenylate cyclase (AC) and play an anti-inflammatory role in chronic obstructive pulmonary disease (COPD). Previously, we have shown that isoforskolin (ISOF) can effectively activate AC1 and AC2 in vitro, improve pulmonary ventilation and reduce the inflammatory response in COPD model rats, supporting that ISOF may be a potential drug for the prevention and treatment of COPD, but the mechanism has not been explored in detail. METHODS: The potential pharmacological mechanisms of ISOF against COPD were analyzed by network pharmacology and multi-omics based on pharmacodynamic study. To use specific agonists, inhibitors and/or SiRNA for gene regulation function studies, combined qPCR, WB were applied to detect changes in mRNA and protein expression of important targets PIK3C3, AKT, mTOR, SPP1 and AQP4 which related to ISOF effect on COPD. And the key inflammatory factors detected by ELISA. RESULTS: Bioinformatics suggested that the anti-COPD pharmacological mechanism of ISOF was related to PI3K-AKT signaling pathway, and suggested target protein like PIK3C3, AQP4, SPP1, AKT, mTOR. Using the AQP4 inhibitor,or inhibiting SPP1 expression by siRNA-SPP1 could block the PIK3C3-AKT-mTOR pathway and ameliorate chronic inflammation. ISOF showed cAMP-promoting effect then suppressed AQP4 expression, together with decreased level of IL-1ß, IL-6, and IL-8. CONCLUSIONS: These findings demonstrate ISOF controlled the cAMP-regulated PIK3C3-AKT-mTOR pathway, thereby alleviating inflammatory development in COPD. The cAMP/AQP4/PIK3C3 axis also modulate Th17/Treg differentiation, revealed potential therapeutic targets for this disease.

Cost-effectiveness analysis of sorafenib, lenvatinib, atezolizumab plus bevacizumab and sintilimab plus bevacizumab for the treatment of advanced hepatocellular carcinoma in China.

BACKGROUND AND OBJECTIVE: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, especially in China. According to the 2021 Chinese Society of Clinical Oncology guidelines, sorafenib, lenvatinib, atezolizumab combined with bevacizumab, and sintilimab combined with bevacizumab are recommended as first-line treatment options for advanced HCC. This study provides a cost-effectiveness analysis of these treatments from the patient perspective. METHODS: A partitioned survival model was established using the TreeAge 2019 software to evaluate the cost-effectiveness. The model includes three states, namely progression-free survival, progressive disease, and death. Clinical data were derived from three randomized controlled studies involving patients with advanced HCC who received the following treatment: sorafenib and lenvatinib (NCT01761266); atezolizumab in combination with bevacizumab (NCT03434379); and sintilimab in combination with bevacizumab (NCT03794440). Cost and clinical preference data were obtained from the literature and interviews with clinicians. RESULTS: All compared with sorafenib therapy, lenvatinib had an incremental cost-effectiveness ratio (ICER) of US$188,625.25 per quality-adjusted life year (QALY) gained; sintilimab plus bevacizumab had an ICER of US$75,150.32 per QALY gained; and atezolizumab plus bevacizumab had an ICER of US$144,513.71 per QALY gained. The probabilistic sensitivity analysis indicated that treatment with sorafenib achieved a 100% probability of cost-effectiveness at a threshold of US$36,600/QALY. One-way sensitivity analysis revealed that the results were most sensitive to the medical insurance reimbursement ratio and drug prices. CONCLUSIONS: In this economic evaluation, therapy with lenvatinib, sintilimab plus bevacizumab, and atezolizumab plus bevacizumab generated incremental QALYs compared with sorafenib; however, these regimens were not cost-effective at a willingness-to-pay threshold of US$36,600 per QALY. Therefore, some patients may achieve preferred economic outcomes from these three therapies by tailoring the regimen based on individual patient factors.

A Review of the Associations Between Obstructive Sleep Apnea and Gestational Diabetes Mellitus and Possible Mechanisms of Disease.

Obstructive sleep apnea (OSA) usually leads to the occurrence of diabetes. Gestational diabetes mellitus (GDM) is a common gestational complication associated with adverse maternal and fetal outcomes. Increasing studies suggest that women with OSA during pregnancy may be at a significantly greater risk of developing GDM. It is crucial to explore the association between OSA and GDM and the mechanisms underlying this association. In this review, we presented a comprehensive literature review of the following: the association between OSA and GDM, the possible mechanisms of this association, and the effects of continuous positive airway pressure (CPAP) on OSA with GDM. The results showed that most authors suggested that there was an association between OSA and GDM. The intermittent hypoxemia (IH) and reduction of slow-wave sleep (SWS) may be the key to this association. IH induces the products of oxidative stress and inflammation as well as dysregulation of the hypothalamic-pituitary-adrenal, which lead to diabetes. In addition, SWS reduction in OSA enhances the inflammation by increasing the inflammatory cytokines, increases the sympathetic activation, and causes changes in leptin level, which result in the development of GDM. Additionally, whether CPAP is beneficial to GDM remains still unclear.

Relative effectiveness of bivalent COVID-19 vaccine: a systematic review and meta-analysis.

Objective: The rapid development of COVID-19 bivalent vaccines (BVs) has encompassed both the original virus strains and the variant strain. However, the effectiveness of BVs is largely unknown. Therefore, we conducted a systematic review and meta-analysis of the effectiveness of BVs. Methods: Literature research was conducted through PubMed, Cochrane Library, Embase, and Web of Science up until November 4, 2023. Both randomized control trials and observational studies were considered for inclusion. Pooled estimates were calculated using a random effects model. The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias in cohort and case-control studies. Results: A total of 1,174 articles were reviewed and 22 eligible studies were included. All included studies were observational (15 cohort studies, 7 case-control studies). The total number of participants was 39,673,160, and the number of people vaccinated with BVs as an intervention group was 11,585,182. Two mRNA BVs were mainly involved, including the ancestral strain and the BA.1 or BA.4-5 variants. Meta-analysis results showed, compared with the monovalent vaccines (MVs), the relative effectiveness (rVE) of the BVs in COVID-19-associated infections/symptomatic infections, illnesses, hospitalizations, and deaths was 30.90% [95% confidence interval (CI), 8.43-53.37], 39.83% (95% CI, 27.34-52.32), 59.70% (95% CI, 44.08-75.32), and 72.23% (95% CI, 62.08-82.38), respectively. For those aged 50 years and older, BVs provided an additional 49.69% (95% CI, 41.44-57.94) effective protection compared with MVs. During the dominance period of the omicron XBB variant strain, BVs provided an additional 47.63% (95% CI, 27.45-67.82) effective protection compared with MVs. Conclusion: Our findings show that the rVE of BVs in preventing COVID-19-associated infections, symptomatic infections, illnesses, hospitalizations, and deaths is higher compared to MVs. Particularly for people over 50 years of age and during the Omicron variant XBB dominance phase, BVs provided superior protection. Therefore, BVs may have a broader application in the prevention and control of coronaviruses variant.

Mechanisms of negative differential resistance in glutamine-functionalized WS2quantum dots.

Understanding the mechanism of the negative differential resistance (NDR) in transition metal dichalcogenides is essential for fundamental science and the development of electronic devices. Here, the NDR of the current-voltage characteristics was observed based on the glutamine-functionalized WS2quantum dots (QDs). The NDR effect can be adjusted by varying the applied voltage range, air pressure, surrounding gases, and relative humidity. A peak-to-valley current ratio as high as 6.3 has been achieved at room temperature. Carrier trapping induced by water molecules was suggested to be responsible for the mechanism of the NDR in the glutamine-functionalized WS2QDs. Investigating the NDR of WS2QDs may promote the development of memory applications and emerging devices.

A retrospective study on the evaluation of the appropriateness of oral anticoagulant therapy for patients with atrial fibrillation.

BACKGROUND: The incidence of atrial fibrillation (AF) is increasing, and effective anticoagulation therapy can prevent adverse events. Selecting the appropriate OAC based on patient characteristics has become a challenge. Interventions are going to be a potential area of focus. OBJECTIVES: To explore the discrepancies between clinician prescriptions and recommended guidelines of oral anticoagulants (OACs) for patients with atrial fibrillation (AF), and to provide direction for improving anticoagulation strategies for treating patients with AF. MATERIALS AND METHODS: Data were collected from the electronic medical record system of Fuwai Yunnan Cardiovascular Hospital between July 2019 and January 2020. The suitability of prescribed OACs for patients with AF was assessed according to the Rules for Avoiding Prescription Inappropriateness, the prescribed medicine label, and any relevant antithrombotic guidelines for treating patients with AF. RESULTS: A total of 460 patients met the inclusion criteria. Of these, 53.7% received an appropriate prescription and 46.3% received an inappropriate prescription. Of the patients who received inappropriate prescriptions, 15.4% were prescribed without the presenting appropriate indicators, 1.3% were prescribed inappropriate drug selection, and 29.6% were prescribed inappropriate drug doses. For patients prescribed without providing appropriate indicators, 2.2% had no indication for medication and 13.3% had an indication for medication, but not a specific OAC. For patients with inappropriate drug selection, 1, 5 patients were on rivaroxaban, dabigatran respectively. The distribution of NOAC doses was as follows: dabigatran standard dose (45.2%), the low dose (54.8%). Rivaroxaban standard dose (58.9%), low dose (36.8%), high dose (4.3%). A total of 44 patients (9.6%) experienced bleeding events, 12 patients (2.6%) experienced embolic events, and 7 patients experienced other adverse events after dosing. CONCLUSIONS: In clinical practice, it is common for patients with AF to receive inappropriate prescriptions of OACs. Therefore there is a need to enhance anticoagulation management in patients with AF to improve the appropriate use of OACs.

Isoforskolin, an adenylyl cyclase activator, attenuates cigarette smoke-induced COPD in rats.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by limited airflow due to pulmonary and alveolar abnormalities from exposure to cigarette smoke (CS). Current therapeutic drugs are limited and the development of novel treatments to prevent disease progression is challenging. Isoforskolin (ISOF) from the plant Coleus forskohlii is an effective activator of adenylyl cyclase (AC) isoforms. Previously we found ISOF could attenuate acute lung injury in animal models, while the effect of ISOF on COPD has not been elucidated. PURPOSE: In this study, we aimed to evaluate the efficacy of ISOF on COPD and reveal its potential mechanisms. METHODS: A rat model of COPD was established by long-term exposure to CS, then the rats were orally administered with ISOF (0.5, 1 and 2 mg/kg). The pulmonary function, lung morphology, inflammatory cells and cytokines in serum or bronchoalveolar lavage fluid (BALF) were evaluated. Transcriptomics, proteomics and network pharmacology analysis were utilized to identify potential mechanisms of ISOF. Droplet digital PCR was used to detect the mRNA expression of AC1-10 in donor lung tissues. AC activation was determined in recombinant human embryonic kidney 293 (HEK293) cells stably expressing human AC isoforms. In addition, ISOF caused trachea relaxation ex vivo were assessed in isolated trachea rings from guinea pigs. RESULTS: ISOF significantly ameliorated pathological damage of lung tissue and improved pulmonary function in COPD rats. ISOF treatment decreased the number of inflammatory cells in peripheral blood, and also the levels of pro-inflammatory cytokines in serum and BALF. Consistent with omics-based analyses, ISOF markedly downregulated the mTOR level in lung tissue. Flow cytometry analysis revealed that ISOF treatment reduced the ratio of Th17/Treg cells in peripheral blood. Furthermore, the expression levels of AC1 and AC2 are relatively higher than other AC isoforms in normal lung tissues, and ISOF could potently activate AC1 and AC2 in vitro and significantly relax isolated guinea pig trachea. CONCLUSION: Collectively, our studies suggest that ISOF exerts its anti-COPD effect by improving lung function, anti-inflammation and trachea relaxation, which may be related to AC activation, mTOR signaling and Th17/Treg balance.

Tianma Formula Alleviates Dementia via ACER2-Mediated Sphingolipid Signaling Pathway Involving Aß.

OBJECTIVE: To reveal the molecular mechanism of the antagonistic effect of traditional Chinese medicine Tianma formula (TF) on dementia including vascular dementia (VaD) and Alzheimer's disease (AD) and to provide a scientific basis for the study of traditional Chinese medicine for prevention and treatment of dementia. METHOD: The TF was derived from the concerted application of traditional Chinese medicine. We detected the pharmacological effect of TF in VaD rats. The molecular mechanism of TF was examined by APP/PS1 mice in vivo, Caenorhabditis elegans (C. elegans) in vitro, ELISA, pathological assay via HE staining, and transcriptome. Based on RNA-seq analysis in VaD rats, the differentially expressed genes (DEGs) were identified and then verified by quantitative PCR (qPCR) and ELISA. The molecular mechanisms of TF on dementia were further confirmed by network pharmacology and molecular docking finally. RESULTS: The Morris water maze showed that TF could improve the cognitive memory function of the VaD rats. The ELISA and histological analysis suggested that TF could protect the hippocampus via reducing tau and IL-6 levels and increasing SYN expression. Meanwhile, it could protect the neurological function by alleviating Aß deposition in APP/PS1 mice and C. elegans. In the RNA-seq analysis, 3 sphingolipid metabolism pathway-related genes, ADORA3, FCER1G, and ACER2, and another 5 nerve-related genes in 45 key DEGs were identified, so it indicated that the protection mechanism of TF was mainly associated with the sphingolipid metabolism pathway. In the qPCR assay, compared with the model group, the mRNA expressions of the 8 genes mentioned above were upregulated, and these results were consistent with RNA-seq. The protein and mRNA levels of ACER2 were also upregulated. Also, the results of network pharmacology analysis and molecular docking were consistent with those of RNA-seq analysis. CONCLUSION: TF alleviates dementia by reducing Aß deposition via the ACER2-mediated sphingolipid signaling pathway.

Donepezil down-regulates propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation in the brain of bilateral common carotid artery occlusion-induced vascular dementia rats.

Vascular dementia (VaD), caused by stroke or small vessel disease, is the second-most common type of dementia after Alzheimer's disease (AD). Donepezil is an acetylcholinesterase inhibitor that is currently used in patients with mild to moderate AD, and has recently been shown to improve cognitive performance in patients with VaD. In this study, we evaluated the effects of donepezil on VaD, and investigated the underlying molecular mechanisms of action. VaD was established by ligation of the bilateral common carotid artery occlusion (BCCAO). Executive function was tested by the Morris water maze (MWM) test and the attentional set shifting task (ASST). Our results showed that donepezil improved executive dysfunction and cognitive flexibility in BCCAO rats. In addition, we showed that donepezil treatment decreased the level of Aß1-42 in BCCAO rats by enzyme-linked immunosorbent assay. Post-translational modifications (PTMs) are known to be critical mechanisms in the regulation of various cellular processes. Furthermore, PTMs have been linked to the central nervous system, which highlights the importance of PTMs in neurodegenerative diseases. In this study, we used western blot analysis to identify several novel PTMs in the hippocampus of BCCAO rats that were treated with or without donepezil. The data revealed that lysine propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation were elevated in the hippocampus of BCCAO rats when compared to sham rats. This increase was abolished by donepezil treatment. Taken together, we speculate that donepezil treatment improves cognitive function in our animal model of VaD, possibly by reducing aberrant acyl-PTMs.

The discovery, design and synthesis of potent agonists of adenylyl cyclase type 2 by virtual screening combining biological evaluation.

Adenylate cyclases (ACs), play a critical role in the conversion of adenosine triphosphate (ATP) into the second messenger cyclic adenosine monophosphate (cAMP). Studies have indicated that adenylyl cyclase type 2 (AC2) is potential drug target for many diseases, however, up to now, there is no AC2-selective agonist reported. In this research, docking-based virtual screening with the combination of cell-based biological assays have been performed for discovering novel potent and selective AC2 agonists. Virtual screening disclosed a novel hit compound 8 as an AC2 agonist with EC50 value of 8.10 µM on recombinant human hAC2 + HEK293 cells. The SAR (structure activity relationship) based on the derivatives of compound 8 was further explored on recombinant AC2 cells and compound 73 was found to be the most active agonist with the EC50 of 90 nM, which is 160-fold more potent than the reported agonist Forskolin and could selectively activate AC2 to inhibit the expression of Interleukin-6. The discovery of a new class of AC2-selective agonists would provide a novel chemical probe to study the physiological function of AC2.

Gastrodin Alleviates Vascular Dementia in a 2-VO-Vascular Dementia Rat Model by Altering Amyloid and Tau Levels.

Vascular dementia (VaD) is the second most common type of dementia and has become a major public health challenge as the global population ages. VaD is caused by cerebrovascular disease, and most patients with VaD have been reported to also have Alzheimer's pathologies, which is the formation of neurofibrillary tangles and amyloid plaques that are mainly composed of hyperphosphorylated Tau and amyloid ß (Aß) respectively. However, the mechanisms of VaD are not completely understood, and very few drugs are available to treat this condition. Gastrodin (Gas) is the main bioactive component of the traditional Chinese herbal plant named Tian Ma (Gastrodia elata), and it has been used to treat neurasthenia in the clinical practice of Chinese Medicine for many years. Here, we hypothesize that Gas alleviates VaD in a rat model of permanent bilateral common carotid artery occlusion (2-VO)-induced VaD. Based on the results of the Morris water maze test and attention set shift test, either 22.5 or 90 mg/kg/day Gas improved the executive dysfunction and memory impairment of 2-VO rats following an intragastric administration for 4 weeks. Both 22.5 and 90 mg/kg/day Gas reduced Aß1-40 and Aß1-42 plaques in plasma and hippocampus of 2-VO rats. Mechanistically, in 2-VO rats, treatment with Gas (90 mg/kg/day) suppressed Aß plaque deposition by decreasing the hippocampus levels of phosphorylated Tau. Thus, Gas ameliorated the cognitive deficits of 2-VO rats by inhibiting the abnormal phosphorylation of Aß and Tau.

Discovery of a potent and selective adenylyl cyclase type 8 agonist by docking-based virtual screening.

Adenylyl cyclases (ACs), which are responsible for catalyzing the conversion of adenosine triphosphate (ATP) into the second messenger cyclic adenosine monophosphate (cAMP), play a critical role in cell signal transduction. In this study, a combined approach involving docking-based virtual screening, with the combination of homology modeling followed by an in-vitro, and cell-based biological assay have been performed for discovering a class of novel potent and selective isoform adenylyl cyclase type 8 (AC8) agonist. The computer-aided virtual screening was used to identify fourteen virtual cluster compounds as potential hits which were further subjected to rigorous bioassays. A novel hit compound VHC-7 (ethyl 3-(2,4-dichlorobenzyl)-2-oxoindoline-3-carboxylate) was identified as a highly potent selective AC8 agonist with EC50 value of 0.1052 ± 0.038 µM. Remarkably, the molecule herein reported can be explored further to discover greater number of hit compounds with better pharmacokinetic properties as well as to serve as a promising novel hit agonist of AC8 for the treatment of various central nervous system disorders and its associated diseases.

Isoforskolin and forskolin attenuate lipopolysaccharide-induced inflammation through TLR4/MyD88/NF-κB cascades in human mononuclear leukocytes.

The principal active component of isoforskolin (ISOF) is from the plant Coleus forskohlii, native to China, which has attracted much attention for its biological effects. We hypothesize that ISOF and forskolin (FSK) pretreatment attenuates inflammation induced by lipopolysaccharide (LPS) related to toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B (NF-κB) signaling. Mononuclear leukocytes (MLs) from healthy donors' blood samples were separated by using density gradient centrifugation. Protein levels of TLR4, MyD88, and NF-κB were detected using western blot and inflammatory cytokines interleukin (IL) 1ß, IL-2, IL-6, IL-21, IL-23, tumor necrosis factor (TNF) α, and TNF-ß were tested by enzyme-linked immunosorbent assay and Quantibody array in MLs. Our results showed that LPS augmented the protein levels of TLR4, MyD88, and NF-κB in MLs and the production of IL-1ß, IL-2, IL-6, IL-21, IL-23, TNF-α, and TNF-ß in supernatants of MLs. Despite treatment with ISOF and FSK prior to LPS, the protein levels of TLR4, MyD88, NF-κB, IL-1ß, IL-2, IL-6, IL-21, IL-23, TNF-α, and TNF-ß in MLs were apparently decreased. roflumilast (RF) and dexamethasone (DM) had a similar effect on MLs with ISOF and FSK. Our results, for the first time, have shown that ISOF and FSK attenuate inflammation in MLs induced by LPS through down-regulating protein levels of IL-1ß and TNF-α, in which TLR4/MyD88/NF-κB signal pathway could be involved.

Repression of Toll-like receptor-4 by microRNA-149-3p is associated with smoking-related COPD.

BACKGROUND: Smoking is the leading cause of COPD. Exploring molecular markers and understanding the pathogenic mechanisms of smoking-related COPD are helpful for early clinical diagnosis and treatment of the disease. This study aims to identify specific circulating microRNAs (miRNAs) from the blood of COPD patients with a long history of smoking. METHODS: Blood samples from four different groups were collected, and miRNA microarray was performed. Differential expression of miRNAs was verified by quantitative polymerase chain reaction. In vitro, THP-1 cells were cultured and stimulated with cigarette smoke extract (CSE) or transfected with miR-149-3p inhibitor/mimics. Protein levels of Toll-like receptor 4 (TLR-4) and nuclear factor κB (NF-κB) were detected using Western blot and immunofluorescence. Interleukin (IL)-1ß and tumor necrosis factor (TNF)-α levels were determined by an enzyme-linked immunosorbent assay. RESULTS: miRNA profiling revealed that the expression of 56 miRNAs was changed between the four groups. Expression of miR-149-3p in group C (non-smoker non-COPD) was higher than in group S (smoker non-COPD), S-COPD (smoker with stable COPD) and AE-COPD (smoker with acute exacerbation COPD). CSE stimulation down-regulated the expression of miR-149-3p and up-regulated the TLR-4 and NF-κB levels in THP-1 cells. Transfecting miR-149-3p inhibitors in THP-1 cells also increased the expression of its target genes. Furthermore, overexpression of miR-149-3p inhibited the TLR-4/NF-κB signaling pathways and reduced the secretion of IL-1ß and TNF-α. CONCLUSION: This study found that smoking can induce differential expression of circulating miR-NAs, such as down-regulation of miR-149-3p. Reducing miR-149-3p may increase the inflammatory response in COPD patients through the regulation of the TLR-4/NF-κB signaling pathway.

Amelioration of cisplatin-induced experimental peripheral neuropathy by a small molecule targeting p75 NTR.

Cisplatin is an effective and widely used first-line chemotherapeutic drug for treating cancers. However, many patients sustain cisplatin-induced peripheral neuropathy (CIPN), often leading to a reduction in drug dosages or complete cessation of treatment altogether. Therefore, it is important to understand cisplatin mechanisms in peripheral nerve tissue mediating its toxicity and identify signaling pathways for potential intervention. Rho GTPase activation is increased following trauma in several models of neuronal injury. Thus, we investigated whether components of the Rho signaling pathway represent important neuroprotective targets with the potential to ameliorate CIPN and thereby optimize current chemotherapy treatment regimens. We have developed a novel CIPN model in the mouse. Using this model and primary neuronal culture, we determined whether LM11A-31, a small-molecule, orally bioavailable ligand of the p75 neurotrophin receptor (p75(NTR)), can modulate Rho GTPase signaling and reduce CIPN. Von Frey filament analysis of sural nerve function showed that LM11A-31 treatment prevented decreases in peripheral nerve sensation seen with cisplatin treatment. Morphometric analysis of harvested sural nerves revealed that cisplatin-induced abnormal nerve fiber morphology and the decreases in fiber area were alleviated with concurrent LM11A-31 treatment. Cisplatin treatment increased RhoA activity accompanied by the reduced tyrosine phosphorylation of SHP2, which was reversed by LM11A-31. LM11A-31 also countered the effects of calpeptin, which activated RhoA by inhibiting SHP2 tyrosine phosphatase. Therefore, suppression of RhoA signaling by LM11A-31 that modulates p75(NTR) or activates SHP2 tyrosine phosphatase downstream of the NGF receptor enhances neuroprotection in experimental CIPN in mouse model.

6,7-seco-ent-kaurane diterpenoids from Isodon sculponeatus with cytotoxic activity.

Six new 6,7-seco-ent-kaurane diterpenoids, sculponeatins N-S (1-6, resp.), together with eleven known analogues, 7-17, were isolated from the aerial parts of Isodon sculponeatus. The structures of compounds 1-6 were elucidated by spectroscopic methods including extensive 1D- and 2D-NMR experiments, as well as HR-ESI-MS analysis. All diterpenoids obtained were assayed for their cytotoxic activity against K562 and HepG2 human tumor cell lines. Among them, compound 1 showed the most significant cytotoxicity with the IC50 values of 0.21 and 0.29 µM, respectively. The structure-activity relationships are discussed.